Regulation of nuclei-specific retinogeniculate targeting

描述（由申请人提供）：突触，允许信息在神经元之间传递的部位，对大脑功能至关重要。即使是由疾病或神经创伤引起的轻微突触异常，也会导致毁灭性的神经系统疾病，这一事实突出了它们的重要性。因此，了解中枢神经系统突触是如何定位、组装和维持（或完善）的，对于我们理解神经系统疾病至关重要。一组突触的形成和细化受到了相当大的关注，是视网膜神经节细胞（RGC），视网膜的输出神经元和大脑内的靶神经元之间形成的突触。在罗杰·斯佩里的化学亲和性假说的推动下（其假设区域化的化学线索指导脑内RGC轴突的地形图绘制），许多研究小组已经寻找并鉴定了视网膜神经节细胞轴突从视网膜正确离开、RGC轴突在视交叉处正确交叉、RGC轴突从非视网膜靶排斥、以及外侧膝状体（LGN）和上级丘（SC）内RGC轴突的地形图。尽管有这些巨大的进步，但仍然不清楚不同类别的视网膜神经节细胞（RGC）-其中有超过22个-如何靶向大脑内功能不同的核团。其中类特异性靶向RGC轴突最明显的一个脑区域是LGN -丘脑中继核，其包含三个结构和功能不同的亚核：腹侧和背侧LGN（分别为vLGN和dLGN）以及将它们分开的膝状体间小叶。由于不同类别的RGCs靶向vLGN和IGL或dLGN，我们假设区域化的指导线索必须存在于LGN中以指导轴突靶向。初步研究已经确定了几个潜在的指导线索，并已证明，一个线索，细胞外基质分子reelin，是必要的retinogeniculate靶向。本建议旨在直接确定reelin是否是必要的核和类特定的目标的LGN的RGC轴突。此外，它建议探索负责reelin依赖性retinogeniculate靶向和靶向缺陷的功能后果，在没有reelin的情况下出现的细胞和分子机制。总之，这里提出的研究将大大提高我们对retinogeniculate电路形成的理解，并将为ECM蛋白在RGC轴突的类特异性靶向中的作用提供新的线索。

DESCRIPTION (provided by applicant): Synapses, the sites that allow information to be passed between neurons, are essential for brain function. Their importance is highlighted by the fact that even minor synaptic abnormalities, caused by disease or neurotrauma, result in devastating neurological conditions. Understanding how CNS synapses are targeted, assembled and maintained (or refined) is therefore essential to our understanding of neurological disorders. One set of synapses whose formation and refinement has received considerable attention are those formed between retinal ganglion cells (RGCs), the output neurons of the retina, and target neurons within the brain. Spurred on by Roger Sperry's postulation of the chemoaffinity hypothesis (which postulated that regionalized chemical cues direct topographic mapping of RGC axons within the brain), many groups have searched for and identified chemical/molecular cues necessary for the correct exiting of retinal ganglion cell axons from the retina, the correct crossing of RGC axons at the optic chiasm, the repulsion of RGC axons from non-retinal targets, and the topographic mapping of RGC axons within the lateral geniculate nucleus (LGN) and superior colliculus (SC). Despite these monumental advances, it still remains unclear how different classes of retinal ganglion cells (RGCs) - of which there are more than 22 - target functionally distinct nuclei within the brain. One brain region where class-specific targeting of RGC axons is most evident is the LGN - a thalamic relay nucleus that contains three structurally and functionally distinct subnuclei: the ventral and dorsal LGN (vLGN and dLGN, respectively) and the intergeniculate leaflet that separates them. Since different classes of RGCs target either vLGN and IGL or dLGN, we hypothesized that regionalized guidance cues must exist in the LGN to direct axonal targeting. Preliminary studies have identified several potential guidance cues and have demonstrated that one cue, the extracellular matrix molecule reelin, is necessary for retinogeniculate targeting. The present proposal aims to directly determine whether reelin is necessary for nuclei- and class-specific target of the LGN by RGC axons. Additionally, it proposes to explore both the cellular and molecular mechanisms responsible for reelin-dependent retinogeniculate targeting and to the function consequences of targeting defects that arise in the absence of reelin. Together, the studies proposed here will substantially progress our understanding of retinogeniculate circuit formation and will shed new light on the role of ECM proteins in class-specific targeting of RGC axons.